NEONATAL SEPSIS - New Born Baby

AIIMS- NICU protocols 2008

Sepsis in the Newborn

M. Jeeva Sankar, Ramesh Agarwal, Ashok K Deorari, Vinod K Paul Division of Neonatology, Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, New Delhi –110029

Address for correspondence: Prof Vinod K Paul Professor Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, New Delhi 110029 Email: [email protected]

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Abstract Infections are the single largest cause of neonatal deaths globally. According to National Neonatal Perinatal Database (2002-03), the incidence of neonatal sepsis in India was 30 per 1000 live-births; klebsiella pneumoniae and staphylococcus aureus were the two most common organisms isolated. Based on the onset, neonatal sepsis is classified into two major categories: early onset sepsis which usually presents with respiratory distress and pneumonia within 72 hours of age and late onset sepsis that usually presents with septicemia and pneumonia after 72 hours of age. Clinical features of sepsis are non-specific in neonates and a high index of suspicion is required for timely diagnosis. Although blood culture is the gold standard for the diagnosis of sepsis, culture reports would be available only after 48-72 hours. A practical septic screen for the diagnosis of sepsis has been described and some suggestions for antibiotic use have been included in the protocol.

Key words: Infections, newborn, sepsis screen, antibiotics.


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1. Introduction Sepsis is the commonest cause of neonatal mortality; it is responsible for about 30-50% of the total neonatal deaths in developing countries1,2. It is estimated that up to 20% of neonates develop sepsis and approximately 1% die of sepsis related causes2. Sepsis related mortality is largely preventable with rational antimicrobial therapy and aggressive supportive care.

2. Epidemiology: Indian data The incidence of neonatal sepsis according to the data from National Neonatal Perinatal Database (NNPD, 2002-03) is 30 per 1000 live births. The database comprising 18 tertiary care neonatal units across India found sepsis to be one of the commonest causes of neonatal mortality contributing to 19% of all neonatal deaths3. Septicemia was the commonest clinical category with an incidence of 23 per 1000 live births while the incidence of meningitis was reported to be 3 per 1000 live births. Among intramural births, Klebsiella pneumoniae was the most frequently isolated pathogen (32.5%), followed by Staphylococcus aureus (13.6%). Among extramural neonates (referred from community/other hospitals), Klebsiella pneumoniae was again the commonest organism (27%), followed by Staphylococcus aureus (15%) and Pseudomonas (13%)3.

3. Definition Neonatal sepsis is a clinical syndrome characterized by signs and symptoms of infection with or without accompanying bacteremia in the first month of life. It encompasses various systemic infections of the newborn such as septicemia, meningitis, pneumonia, arthritis, osteomyelitis, and urinary tract infections. Superficial infections like conjunctivitis and oral thrush are not usually included under neonatal sepsis.


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4. Classification of neonatal sepsis Neonatal sepsis can be classified into two major categories depending up on the onset of symptoms4. Early onset sepsis (EOS): It presents within the first 72 hours of life. In severe cases, the neonate may be symptomatic at birth.

Infants with EOS usually present with respiratory distress and

pneumonia. The source of infection is generally the maternal genital tract. Some maternal / perinatal conditions have been associated with an increased risk of EOS. Knowledge about these potential risk factors would help in early diagnosis of sepsis. Based on the studies from India, the following risk factors seem to be associated with an increased risk of early onset sepsis4, 5: 1. Low birth weight (24 hours. 5. Single unclean or > 3 sterile vaginal examination(s) during labor 6. Prolonged labor (sum of 1st and 2nd stage of labor > 24 hrs) 7. Perinatal asphyxia (Apgar score 10 WBC/mm3 in a 10 mL centrifuged sample (b) >104 organisms /mL in urine obtained by catheterization and (c) any organism in urine obtained by suprapubic aspiration

7. Management 7.1. Supportive: Adequate and proper supportive care is crucial in a sick neonate with sepsis. He/she should be nursed in a thermo-neutral environment taking care to avoid hypo/hyperthermia. Oxygen saturation should be maintained in the normal range; mechanical ventilation may have to be initiated if necessary. If the infant is hemodynamically unstable, intravenous fluids should be administered and the infant is to be monitored for hypo/hyperglycemia. Volume expansion with crystalloids/colloids and judicious use of inotropes are essential to maintain normal tissue perfusion and blood pressure.


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Packed red cells and fresh frozen plasma might have to be used in the event of anemia or bleeding diathesis. 7.2 Antimicrobial therapy: There cannot be a single recommendation for the antibiotic regimen of neonatal sepsis for all settings. The choice of antibiotics depends on the prevailing flora in the given unit and their antimicrobial sensitivity. This protocol does not aim to provide a universal recommendation for all settings but lays down broad guidelines for the providers to make a rational choice of antibiotic combination. Decision to start antibiotics is based upon clinical features and/ or a positive septic screen. However duration of antibiotic therapy is dependent upon the presence of a positive blood culture and meningitis (Table 3). Indications for starting antibiotics: The indications for starting antibiotics in neonates at risk of EOS include any one of the following: (a) presence of >3 risk factors for early onset sepsis (see above) (b) presence of foul smelling liquor (c) presence of ≥2 antenatal risk factor(s) and a positive septic screen and (d) strong clinical suspicion of sepsis. The indications for starting antibiotics in LOS include: (a) positive septic screen and/or (b) strong clinical suspicion of sepsis. Prophylactic antibiotics: We do not use prophylactic antibiotics in the following circumstances: infants on IV fluids/TPN, meconium aspiration syndrome, and after exchange transfusion(s). An exchange transfusion conducted under strict asepsis (single use catheter, sterile gloves, removal of catheter after the procedure) does not increase the risk of sepsis and hence does not merit antibiotics.


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However a messy exchange transfusion could be treated with prophylactic antibiotics. In our unit, ventilated neonates are treated with prophylactic antibiotics for 5-7 days. Choice of antibiotics: Empirical antibiotic therapy should be unit-specific and determined by the prevalent spectrum of etiological agents and their antibiotic sensitivity pattern. Antibiotics once started should be modified according to the sensitivity reports. Guidelines for empirical antibiotic therapy have been provided in Table 4. The empirical choice of antibiotics is dependent upon the probable source of infection. For infections that are likely to be community-acquired where resistant strains are unlikely, a combination of ampicillin or penicillin with gentamicin may be a good choice as a first line therapy. For infections that are acquired during hospital stay, resistant pathogens are likely and a combination of ampicillin or cloxacillin with gentamicin or amikacin may be instituted. In nurseries where this combination is ineffective due to the presence of multiple resistant strains of klebsiella and other gram-negative bacilli, a combination of a third generation cephalosporin (cefotaxime or ceftazidime) with amikacin may be appropriate. 3rd generation cephalosporins have very good CSF penetration and are traditionally thought to have excellent antimicrobial activity against gram negative organisms. Hence they were considered to be a good choice for the treatment of nosocomial infections and meningitis. However, recent reports suggest that at least 60-70% of the gram-ve organisms are resistant to them14-16. More over, routine use of these antibiotics might increase the risk of infections with ESBL (extended spectrum beta-lactamase) positive organisms. Therefore it is preferable to use antibiotics such as piperacillin-tazobactam or methicillin/vancomycin in units with high incidence of resistant strains.

A combination of piperacillin-tazobactam with amikacin should be considered if

pseudomonas sepsis is suspected. Penicillin resistant staphylococcus aureus should be treated with cloxacillin, nafcillin or methicillin. Addition of an aminoglycoside is useful in therapy against


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staphylococcus. Methicillin resistant staphylococcus aureus (MRSA) should be treated with a combination of ciprofloxacin or vancomycin with amikacin. Ciprofloxacin has excellent activity against gram-negative organisms also; however, it does not have good CSF penetration. It may be used for the treatment of resistant gram-negative bacteremia after excluding meningitis. For sepsis due to enterococcus, a combination of ampicillin and gentamicin is a good choice for initial therapy. Vancomycin should be used for the treatment of enterococcus resistant to the first line of therapy. The dosage, route, and frequency of commonly used antibiotics are given in Table 5. Reserve antibiotics: Newer antibiotics like aztreonam, meropenem and imipenem are also now available in the market. Aztreonam has excellent activity against gram-negative organisms while meropenem is effective against most bacterial pathogens except methicillin resistant staphylococcus aureus (MRSA) and enterococcus. Imipenem is generally avoided in neonates because of the reported increase in the incidence of seizures following its use. Empirical use of these antibiotics should be avoided; they should be reserved for situations where sensitivity of the isolated organism warrants its use. 7.3 Adjunctive therapy Exchange transfusion (ET): Sadana et al17 have evaluated the role of double volume exchange transfusion in septic neonates with sclerema and demonstrated a 50% reduction in sepsis related mortality in the treated group. We perform double-volume exchange transfusion with cross-matched fresh whole blood as adjunctive therapy in septic neonates with sclerema. Intravenous Immunoglobulin (IVIG): Non-specific pooled IVIG has not been found to be useful18. Granulocyte-Macrophage colony stimulating factor (GM-CSF): This mode of treatment is still experimental19.


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References 1. Bang AT, Bang RA, Bactule SB, Reddy HM, Deshmukh MD. Effect of home-based neonatal care and management of sepsis on neonatal mortality: field trial in rural India. Lancet 1999;354:1955-61 2. Stoll BJ. The global impact of neonatal infection. Clin Perinatol 1997;24:1-21 3.

Report of the National Neonatal Perinatal Database (National Neonatology Forum) 2002-03.

4. Singh M, Narang A, Bhakoo ON. Predictive perinatal score in the diagnosis of neonatal sepsis. J Trop Pediatr. 1994 Dec;40(6):365-8 5. Takkar VP, Bhakoo ON, Narang A. Scoring system for the prediction of early neonatal infections. Indian Pediatr. 1974;11:597-600 6. Baltimore RS. Neonatal nosocomial infections. Semin Perinatol 1998;22:25-32 7. Wolach

B.

Neonatal

sepsis:

pathogenesis

and

supportive

therapy.

Semin

Perinatol1997;21:28-38 8. Gerdes JS, Polin R. Early diagnosis and treatment of neonatal sepsis. Indian J Pediatr 1998;65:63-78. 9. Polinski C. The value of white blood cell count and differential in the prediction of neonatal sepsis. Neonatal Netw 1996;15:13-23 10. Da Silva O, Ohlsson A, Kenyon C. Accuracy of leukocyte indices and C-reactive protein for diagnosis of neonatal sepsis: a critical review. Pediatr Infect Dis J 1995;14:362-6 11. Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The neonatal blood count in health and disease. I.Refernce values for neutrophilic cells. J Pediatr 1979;95:89-98 12.

Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Revised reference ranges for circulating neutrophils in very-low-birth-weight neonates. Pediatrics 1994;94:76-82.


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13. Sarff LD, Platt LH, McCracken GH Jr. Cerebrospinal fluid evaluation in neonates: Comparison of high-risk neonates with and without meningitis. J Pediatr 1976;88:473-7 14. Upadhyay A, Aggarwal R, Kapil A, Singh S, Paul VK, Deorari AK. Profile of neonatal sepsis in a tertiary care neonatal unit from India: A retrospective study. Journal of Neonatology 2006;20:50-57. 15. Deorari Ashok K. For the Investigators of the National Neonatal Perinatal Database (NNPD). Changing pattern of bacteriologic profile in Neonatal Sepsis among intramural babies. Journal of Neonatology 2006;20:8-15. 16. Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z, Goldmann DA. Hospital-acquired neonatal infections in developing countries. Lancet 2005;365:1175-88. 17. Sadana S, Mathur NB, Thakur A. Exchange transfusion in septic neonates with sclerema: effect on immunoglobulin and complement levels. Indian Pediatr 1997;34:20-5 18. Jenson HB, Pollock HB. The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis. Semin Perinatol 1998;22:50-63 19. Goldman S, Ellis R, Dhar V, Cairo MS. Rationale and potential use of cytokines in the prevention and treatment of neonatal sepsis. Clin Perinatol 1998;25:699-710


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Table 1. A practical sepsis screen Components Total leukocyte count

Abnormal value 0.2

Micro-ESR

>15 mm in 1st hour

C reactive protein (CRP)

>1 mg/dl

(ESR, erythrocyte sedimentation rate)

Table 2. Normal cerebrospinal fluid examination in neonates13 CSF Components Cells/mm3

Normal range 8 (0-30 cells)

PMN (%)

60%

CSF protein (mg/dL)

90 (20-170)

CSF glucose (mg/dL)

52 (34-119)

CSF/ blood glucose (%)

51 (44-248)

(PMN, polymorphonuclear cells; CSF, cerebrospinal fluid)

Table 3. Duration of antibiotic therapy in neonatal sepsis


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Diagnosis

Duration

Meningitis (with or without positive blood/CSF culture)

21 days

Blood culture positive but no meningitis

14 days

Culture negative, sepsis screen positive and clinical course consistent with sepsis

7-10 days

Culture and sepsis screen negative, but clinical course compatible with sepsis

5.7 days


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Table 4. Empirical choice of antibiotics for treatment of neonatal sepsis Clinical situation

Septicemia & Pneumonia

FIRST LINE Community-acquired (Resistant strains unlikely)

Penicillin or Ampicillin and Gentamicin

Add Cefotaxime

SECOND LINE Hospital-acquired Some strains are likely to be resistant

Ampicillin or Cloxacillin and Gentamicin or Amikacin

Add Cefotaxime

THIRD LINE

Cefotaxime or Piperacillin-Tazobactam or Ciprofloxacin and Amikacin;

Hospital-acquired sepsis (Most strains are Likely to be resistant)

Meningitis

Same (Avoid Cipro)

Consider Vancomycin if MRSA is suspected.


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Table 5. Drugs, route of administration and doses of common antibiotics used. Drug

Route

Birth Weight ≤2000g 0-7 d >7 days

Birth Weight >2000g 0-7 days >7 days

Amikacin

I/V, I/M

7.5 q12h

7.5 q8h

10 q12h

10 q8h

Ampicillin Meningitis Others

I/V I/V, I/M

100 q12h 25 q12h

100 q8h 25 q8h

100 q 8h 25 q8h

100 q6h 25 q6h

Cefotoxime Meningitis Others

I/V I/M, I/V

50 q6h 50 q12h

50 q6h 50 q8h

50 q6h 50 q12h

50 q6h 50 q8h

50-100 q12h

50-100 q12h

Piperacillin+ Tazobactam

I/V

Ceftriaxone

I/M, I/V

Ciprofloxacin I/V, PO Cloxacillin Meningitis Others

50-100 q12h 50-100 q8h 50 q24h

50 q24h

50 q24h

75 q24h

10-20 q24h

10-20 q24h

10-20 q12h

10-20 q12h

I/V I/V

50 q12h 25 q12h

50 q8h 25 q8h

50 q8h 25 q8h

50 q6h 25 q6h

Gentamicin Conventional I/V, I/M Single dose I/M

2.5 q12h 4 q24 h

2.5 q8h 4 q24 hr

2.5 q12h 5 q24h

2.5 q8h 5 q24h

Netilmicin

I/V, I/M

2.5 q12h

2.5 q8h

2.5 q12h

2.5 q8h

Penicillin G Meningitis

I/V

Others

I/V, I/M

(units/kg/dose) 75,000 q12h 75,000 q8h -100,000 -1,00,000 25,000 q12h 25,000 q8h

75,000 q8h -1,00,000 25,000 q8h

75,000 q6h -1,00,000 25,000 q6h

15 q12h

15 q12h

15 q8h

Vancomycin I/V

15 q8h

All doses are in mg/kg/dose; (I/V, intravenous; I/M, intramuscular; PO, per-oral; h, hourly)


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Protocol for sepsis Suspected Early Onset Sepsis (EOS)

Suspected Late Onset Sepsis (LOS)

2 antenatal risk factors present or Clinical features suggestive of sepsis

Foul smelling liquor or Presence of >3 antenatal risk factors

Sepsis screen (if negative, repeat after 12 hours) Blood culture Lumbar puncture, chest x-ray (If required)

Blood culture Lumbar puncture

Blood culture Lumbar puncture Abdomen x-ray, urine examination (if required)

Septic screen +ve Start antibiotics

• • • •

No meningitis Cultures sterile Screen negative Clinical course not compatible

Stop antibiotics after 3 days

• • • •

No meningitis Cultures sterile Screen negative Clinical course compatible with sepsis

Treat empirically with antibiotics for 7days

• • • •

No meningitis Cultures sterile Screen positive Clinical course compatible with sepsis

Treat empirically with antibiotics for 7-10 days ntibiotics after 3

• • •

No meningitis Cultures positive Screen +

Antibiotics acc. to sensitivity for 14 days

• • •

Meningitis + Cultures + Screen +

Antibiotics for 21 days

NB. If no response is seen within 48-72 hours of starting treatment, a repeat blood culture should be obtained to determine appropriate choice and duration of antibiotic therapy. A lumbar puncture should be repeated in gram negative meningitis to assess for response to therapy.


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